Explore the vast range of titles available.

Psoriasis (Ps) and psoriatic arthritis (PsA) represent a clinical and immunopathogenic continuum, called psoriatic disease, cumulatively affecting approximately 3% of the general population. Psoriatic disease is a chronic inflammatory disorder affecting the skin and musculoskeletal system. The immuno-pathogenesis is characterized by an activation of the TNF/IL-23/IL-17 cytokine axis, leading to an immunologic imbalance of T-cells resident in all affected tissues, mainly entheses. In the majority of cases, skin Ps predates rheumatological manifestations. Secondary to the higher incidence and the availability of mouse models, there is stronger data available on skin Ps, and data are, in most cases, relevant also to PsA. In a widely accepted model, environmental trigger factors like infections or trauma are capable of initiating an inflammatory cascade, ultimately creating a sustained state of chronic inflammation in genetically susceptible individuals. Besides well-known genetic susceptibility loci, epigenetic DNA modifications, which are associated with Ps development have been characterized recently and will be discussed in this article. The current evidence is promising in the possibility to provide new therapeutic avenues and fill the unmet need of patients, for whom current treatments either do not allow the disease to be controlled or must be continued for life.

Regulatory T cells (Tregs) are a very specialized subset of T lymphocytes: their main function is controlling immune responses during inflammation. T-regs involvement in autoimmune and immune-mediated rheumatic diseases is well-described. Here, we critically review the up-to-date literature findings on the role of Tregs in spondyloarthropathies, particularly in ankylosing spondylitis (AS), a polygenic inflammatory rheumatic disease that preferentially affects the spine and the sacroiliac joints. Genetics discoveries helped in elucidating pathogenic T-regs gene modules and functional involvement. We highlight T-regs tissue specificity as crucial point, as T-regs might have a distinct epigenomic and molecular profiling depending on the different site of tissue inflammation. Furthermore, we speculate about possible therapeutic interventions targeting, or enhancing, Treg cells in spondyloarthropathies.

Genomic predisposition cannot explain the onset of complex diseases, as well illustrated by the largely incomplete concordance among monozygotic twins. Epigenetic mechanisms, including DNA methylation, chromatin remodelling and non-coding RNA, are considered to be the link between environmental stimuli and disease onset on a permissive genetic background in autoimmune and chronic inflammatory diseases. The paradigmatic cases of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjogren’s syndrome (SjS) and type-1 diabetes (T1D) share the loss of immunological tolerance to self-antigen influenced by several factors, with a largely incomplete role of individual genomic susceptibility. The most widely investigated epigenetic mechanism is DNA methylation which is associated with gene silencing and is due to the binding of methyl-CpG binding domain (MBD)-containing proteins, such as MECP2, to 5-methylcytosine (5mC). Indeed, a causal relationship occurs between DNA methylation and transcription factors occupancy and recruitment at specific genomic locus. In most cases, the results obtained in different studies are controversial in terms of DNA methylation comparison while fascinating evidence comes from the comparison of the epigenome in clinically discordant monozygotic twins. In this manuscript, we will review the mechanisms of epigenetics and DNA methylation changes in specific immune-mediated rheumatic diseases to highlight remaining unmet needs and to identify possible shared mechanisms beyond different tissue involvements with common therapeutic opportunities.Key Points• DNA methylation has a crucial role in regulating and tuning the immune system.• Evidences suggest that dysregulation of DNA methylation is pivotal in the context of immune-mediated rheumatic diseases.• DNA methylation dysregulation in FOXP3 and interferons-related genes is shared within several autoimmune diseases.• DNA methylation is an attractive marker for diagnosis and therapy.

Psoriatic arthritis (PsA) is a chronic inflammatory disease belonging to the family of spondyloarthropathies (SpA). PsA commonly aggravates psoriasis of the skin and frequently manifests as an oligoarthritis with axial skeletal involvement and extraarticular manifestations including dactylitis, enthesitis, and uveitis. The weight of genetic predisposition to psoriasis and PsA is illustrated by the concordance rates in monozygotic twins which clearly demonstrate that genomics is insufficient to induce the clinical phenotype. The association of PsA with several single nucleotide polymorphisms (SNPs) at the IL23R locus and the involvement of Th17 cells in the immunopathogenesis of PsA clearly put the IL-23/IL-17 axis in the spotlight. The IL-23 and IL-17 cytokines have a pivotal role in the chronic inflammation of the synovium in PsA and are also prominent in the skin lesions of those with PsA. In this review, we focus on the genetic association of the IL-23/IL-17 axis with PsA and the contribution of these master cytokines in the pathophysiology of the disease, highlighting the main cell types incriminated in PsA and their specific role in the peripheral blood, lesional skin and joints of patients. We then provide an overview of the approved biologic drugs targeting the IL-23/IL-17 axis and discuss the advantages of genetic stratification to enhance personalized therapies in PsA.

Th17 responses are critical to a variety of human autoimmune diseases, and therapeutic targeting with monoclonal antibodies against IL-17 and IL-23 has shown considerable promise. Here, we report data to support selective bromodomain blockade of the transcriptional coactivators CBP (CREB binding protein) and p300 as an alternative approach to inhibit human Th17 responses. We show that CBP30 has marked molecular specificity for the bromodomains of CBP and p300, compared with 43 other bromodomains. In unbiased cellular testing on a diverse panel of cultured primary human cells, CBP30 reduced immune cell production of IL-17A and other proinflammatory cytokines. CBP30 also inhibited IL-17A secretion by Th17 cells from healthy donors and patients with ankylosing spondylitis and psoriatic arthritis. Transcriptional profiling of human T cells after CBP30 treatment showed a much more restricted effect on gene expression than that observed with the pan-BET (bromo and extraterminal domain protein family) bromodomain inhibitor JQ1. This selective targeting of the CBP/p300 bromodomain by CBP30 will potentially lead to fewer side effects than with the broadly acting epigenetic inhibitors currently in clinical trials.

Ankylosing spondylitis (AS) is a common form of inflammatory spinal arthritis with a complex polygenic aetiology. Genome-wide association studies have identified more than 100 loci, including some involved in antigen presentation ( HLA-B27 , ERAP1 , and ERAP2 ), some in Th17 responses ( IL6R, IL23R, TYK2 , and STAT3 ), and others in macrophages and T-cells ( IL7R, CSF2 , RUNX3 , and GPR65 ). Such observations have already helped identify potential new therapies targeting IL-17 and GM-CSF. Most AS genetic associations are not in protein-coding sequences but lie in intergenic regions where their direct relationship to particular genes is difficult to assess. They most likely reflect functional polymorphisms concerned with cell type-specific regulation of gene expression. Clarifying the nature of these associations should help to understand the pathogenic pathways involved in AS better and suggest potential cellular and molecular targets for drug therapy. However, even identifying the precise mechanisms behind the extremely strong HLA-B27 association with AS has so far proved elusive. Polygenic risk scores (using all the known genetic associations with AS) can be effective for the diagnosis of AS, particularly where there is a relatively high pre-test probability of AS. Genetic prediction of disease outcomes and response to biologics is not currently practicable.

The term spondyloarthritis (SpA) encompasses a heterogeneous group of inflammatory musculoskeletal diseases with several common genetic background and clinical features, including the possible involvement of the axial skeleton with peripheral mono- or oligo- arthritis and frequently coexisting skin, eye and intestinal manifestations. When the sacroiliac joints or other parts of the spine or thoracic wall are predominantly affected at magnetic resonance or X-ray imaging with inflammatory back pain, the disease is classified as axial SpA and the therapeutic choices are significantly different compared to cases of peripheral arthritis. Moving from the narrow effectiveness and safety profiles of non-steroidal anti-inflammatory drugs, there has been a significant research effort aimed at identifying new treatments based on our better understanding of the pathogenesis of SpA. Indeed, in parallel with the solid data demonstrating that IL-17 and IL-23 are key cytokines in the development of enthesitis and spondylitis, monoclonal antibodies interfering with this pathway have been developed for the treatment of axial SpA. Furthermore, the IL-17/IL-23 axis is key to extra-articular manifestations such as inflammatory bowel disease, uveitis, and psoriasis which are frequent comorbidities of SpA. Currently available drugs act through these mechanisms recognizing IL-23 and targeting IL-17, such as secukinumab and ixekizumab. These therapeutic approaches are now envisioned in the international treatment recommendations for psoriatic arthritis with an axial phenotype as well as for ankylosing spondylitis (AS). We will provide herein a concise comprehensive overview of the clinical evidence supporting the use of these and other drugs acting on IL-23 and IL-17 in axial SpA.

Editorial on the Research TopicRole of the IL-23/IL-17 Pathway in Chronic Immune-Mediated Inflammatory Diseases: Mechanisms and Targeted TherapiesChronic inflammatory diseases (CID) are clinically heterogeneous conditions that share common inflammatory pathways and derive from aberrant immune responses. The implication of the interleukin-23/interleukin-17 (IL-23/IL-17) axis in several CID is supported by studies in animal models of autoimmune disease (1, 2) and by the genome-wide association studies (GWAS) finding that several of the non-MHC loci genetically linked to Crohn’s disease, psoriasis, and axial spondyloarthritis (axSpA), are associated with genes in this pathway (IL23R, IL12B, IL6R, IL1R2, RORC, RUNX3, TYK2, JAK2, CARD9) (3–5).